We propose to determine whether the agent of human granulocytic ehrlichiosis in coastal New England is cotransmitted with those of Lyme disease and human babesiosis. An Ehrlichia with molecular identity to one infecting humans in the upper Midwest was isolated from a Nantucket resident by subinoculation of her blood into laboratory mice. This agent stably infects intact or splenectomised outbred and inbred mice, as well as Peromyscus leucopus, the main enzootic reservoir of Borrelia burgdorferi and Babesia microti in the northeastern U.S. Nymphal deer ticks that had fed as larvae on experimentally infected mice transmitted the agent to uninfected mice, definitively demonstrating vector competence. Thus, we shall 1) determine the mode of perpetuation of the HGE agent in coastal Massachusetts, focusing on the hypothesis that borreliae, babesiae, and ehrlichiae share an enzootic cycle between rodent reservoirs and the deer tick vector; 2) refine our methods for detecting evidence of HGE infection in vertebrate and tick hosts, comparing microscopy-based methods (including immunohistochemistry) with a polymerase chain reaction assay; and 3) describe the public health burden of this emergent zoonosis relative to that of Lyme disease and babesiosis in various coastal New England communities, by retrospective analysis of a large serum bank, as well as by prospective cohort study. Together, these studies are designed to describe how humans become infected by this new zoonotic agent, and provide a basis for intervention.